WO2008080973A1 - Dérivés d'oxindole substitués et leur utilsiation comme lignads du récepteur de la vasopressine - Google Patents

Dérivés d'oxindole substitués et leur utilsiation comme lignads du récepteur de la vasopressine Download PDF

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Publication number
WO2008080973A1
WO2008080973A1 PCT/EP2007/064622 EP2007064622W WO2008080973A1 WO 2008080973 A1 WO2008080973 A1 WO 2008080973A1 EP 2007064622 W EP2007064622 W EP 2007064622W WO 2008080973 A1 WO2008080973 A1 WO 2008080973A1
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Prior art keywords
general formula
pharmaceutically acceptable
compound
treatment
prodrug
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PCT/EP2007/064622
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English (en)
Inventor
Astrid Netz
Thorsten Oost
Hervé Geneste
Wilfried Martin Braje
Wolfgang Wernet
Liliane Unger
Wilfried Hornberger
Wilfried Lubisch
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Abbott Gmbh & Co. Kg
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Priority to NZ577720A priority Critical patent/NZ577720A/en
Application filed by Abbott Gmbh & Co. Kg filed Critical Abbott Gmbh & Co. Kg
Priority to MX2009007104A priority patent/MX2009007104A/es
Priority to JP2009543480A priority patent/JP5318781B2/ja
Priority to US12/521,713 priority patent/US8815868B2/en
Priority to BRPI0720866-9A2A priority patent/BRPI0720866A2/pt
Priority to CN200780051459.2A priority patent/CN101611028B/zh
Priority to AU2007341236A priority patent/AU2007341236B2/en
Priority to UAA200908025A priority patent/UA96785C2/uk
Priority to ES07866324.2T priority patent/ES2523320T3/es
Priority to EP07866324.2A priority patent/EP2114923B1/fr
Priority to CA2673584A priority patent/CA2673584C/fr
Priority to KR1020097016052A priority patent/KR101485326B1/ko
Publication of WO2008080973A1 publication Critical patent/WO2008080973A1/fr
Priority to IL199265A priority patent/IL199265A/en
Priority to ZA2009/04363A priority patent/ZA200904363B/en
Priority to HK10100154.0A priority patent/HK1132740A1/xx
Priority to US13/590,261 priority patent/US8859557B2/en
Priority to US14/481,847 priority patent/US20140378471A1/en
Priority to US14/740,598 priority patent/US20150352110A1/en

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Definitions

  • the present invention relates to novel substituted oxindole derivatives, to medicaments comprising them and to their use for treating diseases.
  • Vasopressin is an endogenous hormone which exerts widely diverse effects on organs and tissues. It is suspected that the vasopressin system is involved in various pathological states such as, for example, heart failure and high blood pressure. At present three receptors (Via, V1 b or V3 and V2) via which vasopressin mediates its numerous effects are known. Antagonists of these receptors are therefore being investigated as possible novel therapeutic approaches to the treatment of diseases (M. Thibonnier, Exp.Opin. Invest. Drugs 1998, 7(5), 729-740).
  • the present application describes novel substituted oxindoles carrying an arylsulphonyl group in position 1.
  • 1-Phenylsulphonyl-1 ,3-dihydro-2/-/-indol-2-ones have previously been described as ligands of vasopressin receptors.
  • WO 93/15051 WO95/18105, WO 98/25901 , WO 01/55130, WO 01/55134, WO 01/64668 and WO 01/98295 describe derivatives derived from the oxindole skeleton and having arylsulphonyl groups in position 1. These compounds differ essentially in the substitution in position 3.
  • WO 93/15051 and WO 98/25901 describe 1-phenylsulphonyl-1 ,3-dihydro- 2/-/-indol-2-ones in which the oxindole structure is substituted in position 3 by two alkyl radicals which may also together form a cycloalkyl radical (spiro linkage) as ligands of vasopressin receptors.
  • the spiro ring may comprise heteroatoms, such as oxygen and nitrogen (optionally with substituents).
  • WO 95/18105 describes 1-phenylsulphonyl-1 ,3-dihydro-2H-indol-2-ones having a nitrogen atom in position 3 as ligands of vasopressin receptors.
  • radicals which are selected from the group consisting of alkyl, cycloalkyl, phenyl and benzyl are attached in position 3 (in each case optionally with substituents).
  • WO 03/008407 describes 1-phenylsulphonyloxindoles in which pyridylpiperazines are attached via an oxycarbonyl group to the oxindole in position 3.
  • WO 2005/030755 describes as Example 108, the carbamate compound 4-(1- methylpiperidin-4-yl)piperazine-1 -carboxylic acid 5-cyano-1 -(2,4-dimethoxy- phenylsulphonyl)-3-(2-methoxypyridin-3-yl)-2-oxo-2,3-dihydro-1 H-indol-3-yl ester (according to IUPAC nomenclature: 5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2- methoxypyridin-3-yl)-2-oxo-2,3-dihydro-1 /-/-indol-3-yl 4-(1 -methylpiperidin-4-yl)piperazine- 1-carboxylate).
  • WO 06/005609 describes the 2-ethoxyphenyl urea compounds ⁇ /-[5-cyano-1-[(2,4- dimethoxyphenyl)sulphonyl]-3-(2-ethoxyphenyl)-2-oxo-2,3-dihydro-1 /-/-indol-3-yl]-4-(1- methylpiperidin-4-yl)piperazine-1-carboxamide (as Example 1 19) and ⁇ /-[5-cyano-1-[(2,4- dimethoxyphenyl)sulphonyl]-3-(2-ethoxyphenyl)-2-oxo-2,3-dihydro-1 H-indol-3-yl]-4-(4- methylpiperazin-1-yl)piperidine-1-carboxamide (as Example 128).
  • vasopressin V1 b receptor binding affinity to the vasopressin V1 b receptor
  • further properties may be advantageous in the treatment and/or prophylaxis of vasopressin-dependent disorders, such as, for example:
  • a selectivity for the vasopressin V1 b receptor over the vasopressin Vi a receptor i.e. the quotient of the binding affinity to the V1 a receptor (Ki(VI a) (determined in the unit “nanomolar (nM)") and the binding affinity to the V1 b receptor (Ki(VI b)) (determined in the unit "nanomolar (nM)").
  • Ki(VI a) determined in the unit "nanomolar (nM)
  • nM nanomolar (nM)
  • a selectivity for the vasopressin V1 b receptor over the vasopressin V2 receptor i.e. the quotient of the binding affinity to the V2 receptor (Ki(V2) (determined in the unit “nanomolar (nM)") and the binding affinity to the V1 b receptor (Ki(VI b)) (determined in the unit "nanomolar (nM)").
  • Ki(V2) determined in the unit "nanomolar (nM)
  • V1 b receptor Ki(VI b)
  • nM nanomolar (nM)
  • Ki(VI b) the binding affinity to the V1 b receptor
  • cytochrom P450 is the name for a superfamily of haem proteins having enzymatic activity (oxidases). They are also of particular importance for the degradation (metabolism) of foreign substances, such as pharmaceutics or xenobiotics, in mammalian organisms.
  • CYP 1 A2 CYP 2C9, CYP 2D6 and CYP 3A4.
  • CYP 3A4 inhibitors for example grapefruit juice, cimetidine, erythromycin
  • medicaments which are degraded via this enzyme system and which thus compete for the same binding site at the enzyme are administered simultaneously, their degradation may be slowed down, and actions and side-effects of the medicament administered may be enhanced in an unwanted manner;
  • suitable pharmacokinetics temporary profile of the concentration of the compound according to the invention in the plasma or in tissues, for example brain). Pharmacokinetics may be described by the following parameters: half-life, distribution volume, plasma clearance, AUC ("area under the curve", area under the concentration- time curve), oral bioavailability, the brain/plasma ratio;
  • the blockage of the hERG channel may be measured by electrophysical experiments using cells transfected with the hERG channel, by "whole-cell patch clamping" (GJ. Diaz et al., Journal of Pharmacological and Toxicological Methods, 50 (2004), 187-199).
  • the substance according to the invention should have one or more of the advantages 1.) to 9.) mentioned above, in particular a suitable selectivity for the V1 b receptor over the Via receptor.
  • R1 is ethoxy
  • R2 is hydrogen
  • R3 is cyano
  • R4 is hydrogen
  • R5 is hydrogen , methoxy or ethoxy
  • R6 is hydrogen or methoxy
  • R7 is hydrogen , methyl, ethyl, n-propyl or isopropyl
  • X1 is -NH-
  • X2 is N or CH
  • X3 is N or CH
  • X2 and X3 are not simultaneously N (that is to say are a nitrogen atom); and by the pharmaceutically acceptable salts, tautomeric forms, and prodrugs thereof.
  • the present invention relates to compounds of the general formula (I) (also “compounds (I)” below), including the tautomeric forms thereof, and the pharmaceutically acceptable salts of the compounds (I) and the prodrugs of the compounds (I).
  • a preferred subject-matter of the invention are compounds of the general formula (I) in which
  • R1 is ethoxy
  • R2 is hydrogen
  • R3 is cyano
  • R4 is hydrogen
  • R5 is hydrogen or methoxy, in particular methoxy
  • R6 is hydrogen or methoxy, in particular methoxy
  • R7 is hydrogen, methyl, ethyl, n-propyl or isopropyl
  • X1 is -NH-
  • X2 is N or CH; X3 is N or CH; where X2 and X3 are not simultaneously a nitrogen atom; and the pharmaceutically acceptable salts, tautomeric forms, and prodrugs thereof.
  • a particularly preferred subject-matter of the invention are compounds of the general formula (I) in which
  • R1 is ethoxy
  • R2 is hydrogen
  • R3 is cyano
  • R4 is hydrogen
  • R5 is hydrogen or methoxy, in particular methoxy
  • R6 is hydrogen or methoxy, in particular methoxy, in particular methyl or ethyl
  • R7 is hydrogen, methyl or ethyl
  • X1 is -NH-
  • X2 is N; X3 is CH; and the pharmaceutically acceptable salts, tautomeric forms, and prodrugs thereof.
  • a further particularly preferred subject-matter of the invention are compounds of the general formula (I) in which R1 is ethoxy; R2 is hydrogen; R3 is cyano;
  • R4 is hydrogen
  • R5 is hydrogen or methoxy, in particular methoxy
  • R6 is hydrogen or methoxy, in particular methoxy
  • R7 is hydrogen , methyl or ethyl, in particular methyl or ethyl;
  • X1 is -NH-
  • X2 is CH
  • X3 is N; and the pharmaceutically acceptable salts, tautomeric forms, and prodrugs thereof.
  • a further particularly preferred subject-matter of the invention are compounds of the general formula (I) in which
  • R1 is ethoxy
  • R2 is hydrogen; R3 is cyano;
  • R4 is hydrogen
  • R5 is hydrogen or methoxy, in particular methoxy
  • R6 is hydrogen or methoxy, in particular methoxy
  • R7 is hydrogen, methyl or ethyl, in particular methyl or ethyl;
  • X1 is -NH-;
  • X2 is CH
  • X3 is CH; and the pharmaceutically acceptable salts, tautomeric forms, and prodrugs thereof.
  • a further particularly preferred subject-matter of the invention are compounds of the general formula (I) in which
  • R1 is ethoxy
  • R2 is hydrogen
  • R3 is cyano
  • R4 is hydrogen
  • R5 is methoxy
  • R6 is methoxy
  • R7 is methyl or ethyl
  • X1 is -NH-
  • X2 is CH and X3 is N;
  • X2 is N and X3 is CH; and the pharmaceutically acceptable salts, tautomeric forms, and prodrugs thereof.
  • Examples of preferred embodiments of the present invention are compounds according to the general formula (I), and the pharmaceutically acceptable salts, tautomeric forms, and prodrugs thereof, in which R1 is ethoxy, R2 is hydrogen, R3 is cyano, R4 is hydrogen, X1 is NH, and in which the radicals X2, X3, R5, R6 and R7 have in each case the meanings listed in one of the rows of Table 1 below.
  • the present invention relates to the following compound of the formula Ia (which corresponds to compound Example 1 of table 1 )
  • the present invention also relates to the compound Example 7 of table 1 and also to the pharmaceutically acceptable salts, tautomeric forms, and prodrugs thereof.
  • the present invention also relates to the compound Example 31 of table 1 and also to the pharmaceutically acceptable salts, tautomeric forms, and prodrugs thereof.
  • the present invention also relates to the compound Example 37 of table 1 and also to the pharmaceutically acceptable salts, tautomeric forms, and prodrugs thereof.
  • the compounds (I) or (Ia) of the invention have a centre of chirality in position 3 of the 2- oxindole ring.
  • the compounds according to the invention of the general formula (I) or (Ia) may therefore be present as a 1 :1 mixture of enantiomers (racemate), or as a non- racemic mixture of enantiomers in which one of the two enantiomers, i.e. either the
  • (laevorotatory) enantiomer which turns the plane of polarization of linear polarized light to the left ((-)-enantiomer below), or the (dextrorotatory) enantiomer which turns the plane of polarization of linear polarized light to the right ((+)-enantiomer below), is enriched, or as essentially enantiomerically pure compounds (enantiomeric excess ee > 90%), i.e. as essentially enantiomerically pure (-)-enantiomer or (+)-enantiomer.
  • the compounds are present as essentially enantiomerically pure compounds. Particular preference is given to compounds which are essentially enantiomerically pure (ee > 90%).
  • the invention therefore provides the pure enantiomers as well as their mixtures, for example, mixtures in which one enantiomer is present in enriched form, but also the racemates.
  • the invention also provides the pharmaceutically acceptable salts, the tautomers and the prodrugs of the pure enantiomers of (I) or (Ia), and the enantiomer mixtures in the form of the pharmaceutically acceptable salts, the tautomers and the prodrugs of (I) or (Ia).
  • Preferred embodiments of the invention are compounds of the general formula (I) or (Ia), as defined above, which are characterized in that they are present in optically active form and that they are in each case the enantiomer, which rotates the plane of polarization of polarized light to the left, (i.e. the laevorotatory enantiomer) of the compound of the general formula (I) in question in the form of the free base, or a pharmaceutically acceptable salt, a tautomeric form or a prodrug thereof.
  • the laevorotatory enantiomers of the compounds (I) or (Ia) are also referred to as (-)-enantiomers.
  • Preferred embodiments of the invention are those compounds of the general formula (I) or (Ia), as defined above, which are characterized in that they are present in optically active form, where the absolute configuration of the chiral C-3 ring carbon atom of these compounds corresponds to the absolute configuration at C-3 of the (-)-enantiomer of the compound of the formula (Ia) in the form of the free base.
  • This configuration is also referred to below as the "preferred configuration”.
  • X-Ray structure analyses have shown that the (-)-enantiomer of the compounds of the formula (Ia) has S configuration with respect to the centre of asymmetry at the carbon atom of position 3 of the oxindole ring.
  • preferred embodiments of the invention are compounds of the general formula (I) or (Ia) as defined above, which are characterized in that they are present in optically inactive form, that is to say in the form of the racemate, or in the form of a pharmaceutically acceptable salt, a tautomeric form or a prodrug of the racemate.
  • a further subject-matter of the present invention relates to medicaments comprising at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof as defined above.
  • a further subject-matter of the present invention relates to compounds of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof as defined above for use as a medicament.
  • a further subject-matter of the present invention relates to the compounds of the formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof as defined above for use in therapy or prophylaxis of a disease, in particular a vasopressin-dependent disease or a disease mentioned herein.
  • a further subject-matter of the present invention relates to the use of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof as defined above for the treatment and/or prophylaxis of at least one vasopressin-dependent disease and/or for the manufacture of a medicament for the treatment and/or a prophylaxis of at least one vasopressin-dependent disease.
  • Vasopressin-dependent diseases are those in which the progression of the disease depends at least in part on vasopressin, i.e. diseases where the vasopressin level, which may contribute directly or indirectly to the disease picture, is elevated.
  • the present invention also relates to the use of the compounds (I) or (Ia) according to the invention and/or a pharmaceutically acceptable salt or a prodrug thereof for the treatment and/or prophylaxis of diseases in which the progression of the disease depends at least in part on vasopressin, i.e. diseases where the vasopressin level, which may contribute directly or indirectly to the disease picture, is elevated.
  • the present invention also relates to the use of the compounds (I) or (Ia) according to the invention and/or a pharmaceutically acceptable salt or a prodrug thereof for preparing a medicament for the treatment and/or prophylaxis of such a disease.
  • the present invention relates in particular to the use of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof as defined above for the treatment and/or prophylaxis of at least one disorder selected from the group consisting of diabetes, in particular diabetes insipidus, insulin resistance, nocturnal enuresis, incontinence, diseases in which blood coagulation disorders occur, and/or for delaying micturition and the use thereof for the manufacture of a medicament for the treatment and/or prophylaxis of at least one of said diseases.
  • diabetes in particular diabetes insipidus, insulin resistance, nocturnal enuresis, incontinence, diseases in which blood coagulation disorders occur, and/or for delaying micturition and the use thereof for the manufacture of a medicament for the treatment and/or prophylaxis of at least one of said diseases.
  • the present invention relates in particular to the use of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof as defined above for the treatment and/or prophylaxis of at least one disorder selected from the group consisting of hypertension, pulmonary hypertension, heart failure, myocardial infarction, coronary spasm, unstable angina, PTCA (percutaneous transluminal coronary angioplasty), ischemias of the heart, disorders of the renal system, edemas, renal vasospasm, necrosis of the renal cortex, hyponatremia, hypokalemia, Schwartz-Bartter syndrome, disorders of the gastrointestinal tract, gastritic vasospasm, hepatocirrhosis, gastric and intestinal ulcer, emesis, emesis occurring during chemotherapy, and travel sickness, and the use thereof for the manufacture of a medicament for the treatment and/or prophylaxis of at least one of said diseases.
  • PTCA percutaneous
  • the compounds (I) or (Ia) of the invention, their salts, their tautomers and their prodrugs can also be used for the treatment of various vasopressin-dependent complaints which exhibit central nervous causes or alterations in the HPA axis (hypothalamic pituitary adrenal axis), for example for affective disorders such as depressive disorders and bipolar disorders. These include for example dythymic disorders, phobias, post-traumatic stress disorders, general anxiety disorders, panic disorders, seasonal depressions and sleep disorders.
  • the compounds (I) or (Ia) of the invention, their salts, their tautomers and their prodrugs can likewise be employed for treatment in cases of anxiety disorders and stress- dependent anxiety disorders such as, for example, generalized anxiety disorders, phobias, post-traumatic anxiety disorders, panic anxiety disorders, obsessive-compulsive anxiety disorders, acute stress-dependent anxiety disorders and social phobia.
  • the compounds of the invention can further be employed also for the treatment of memory impairments, Alzheimer's disease, psychoses, psychotic disorders, sleep disorders and/or Cushing's syndrome, and all stress-dependent diseases.
  • a further subject-matter of the invention relates to the use of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof as defined above for the treatment of affective disorders and/or for the manufacture of a medicament for the treatment of affective disorders.
  • a further subject-matter of the invention relates to the use of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof as defined above for the treatment of anxiety disorders and/or stress-dependent anxiety disorders and/or for the manufacture of a medicament for the treatment of anxiety disorders and/or stress-dependent anxiety disorders.
  • a further subject-matter of the invention relates to the use of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof as defined above for the treatment of memory impairments and/or Alzheimer's disease and/or for the manufacture of a medicament for the treatment of memory impairments and/or Alzheimer's disease.
  • a further subject-matter of the invention relates to the use of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof as defined above for the treatment of psychoses and/or psychotic disorders and/or for the manufacture of a medicament for the treatment of psychoses and/or psychotic disorders.
  • a further subject-matter of the invention relates to the use of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof as defined above for the treatment of Cushing's syndrome or other stress-dependent diseases and/or for the manufacture of a medicament for the treatment of Cushing's syndrome or other stress-dependent diseases.
  • a further subject-matter of the invention relates to the use of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof as defined above for the treatment of sleep disorders and/or for the manufacture of a medicament for the treatment of sleep disorders.
  • a further subject-matter of the invention relates to the use of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof as defined above for the treatment of depressive disorders and/or for the manufacture of a medicament for the treatment of depressive disorders.
  • a further subject-matter of the invention relates to the use of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof as defined above for the treatment of childhood onset mood disorders and/or for the manufacture of a medicament for the treatment of childhood onset mood disorders.
  • the term "childhood onset mood disorders” is understood to mean mood disorders and depressions which begin as early as childhood.
  • a further subject-matter of the invention relates to the use of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof as defined above for the treatment of vasomotor symptoms and/or thermoregulatory dysfunctions, such as, for example, the "hot flush" symptom.
  • a further subject-matter of the invention relates to the use of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof as defined above for the treatment and/or prophylaxis of drug dependencies, medicament dependencies and/or dependencies mediated by other factors, for the treatment and/or prophylaxis of stress caused by the withdrawal of one or more factors mediating the dependency and/or for the treatment and/or prophylaxis of stress-induced relapses into the drug dependencies, medicament dependencies and/or dependencies mediated by other factors.
  • a further subject-matter of the invention relates to the use of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof as defined above for the treatment and/or prophylaxis of schizophrenia and/or psychosis.
  • a further subject-matter of the invention relates to a method for the treatment and/or prophylaxis of at least one disorder selected from the group consisting of diabetes, in particular diabetes insipidus, insulin resistance, nocturnal enuresis, incontinence, diseases in which blood coagulation disorders occur, and for delaying micturition in a patient, characterized in that an effective amount of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof is administered to the patient.
  • a further subject-matter of the invention relates to a method for the treatment and/or prophylaxis of at least one disorder selected from the group consisting of hypertension, pulmonary hypertension, heart failure, myocardial infarction, coronary spasm, unstable angina, PTCA (percutaneous transluminal coronary angioplasty), ischemias of the heart, disorders of the renal system, edemas, renal vasospasm, necrosis of the renal cortex, hyponatremia, hypokalemia, Schwartz-Bartter syndrome, disorders of the gastrointestinal tract, gastritic vasospasm, hepatocirrhosis, gastric and intestinal ulcer, emesis, emesis occurring during chemotherapy, and travel sickness in a patient, characterized in that an effective amount of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof is administered to the patient.
  • PTCA percutaneous transluminal coronary angioplasty
  • a further subject-matter of the invention relates to a method for the treatment and/or prophylaxis of affective disorders in a patient, characterized in that an effective amount of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof is administered to the patient.
  • a further subject-matter of the invention relates to a method for the treatment of anxiety disorders and/or stress-dependent anxiety disorders in a patient, characterized in that an effective amount of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof is administered to the patient.
  • a further subject-matter of the invention relates to a method for the treatment of memory impairments and/or Alzheimer's disease in a patient, characterized in that an effective amount of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof is administered to the patient.
  • a further subject-matter of the invention relates to a method for the treatment of psychoses and/or psychotic disorders in a patient, characterized in that an effective amount of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof is administered to the patient.
  • a further subject-matter of the invention relates to a method for the treatment of Cushing's syndrome in a patient, characterized in that an effective amount of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof is administered to the patient.
  • a further subject-matter of the invention relates to a method for the treatment of sleep disorders in a patient, characterized in that an effective amount of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof is administered to the patient.
  • a further subject-matter of the invention relates to a method for the treatment of depressive disorders in a patient, characterized in that an effective amount of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof is administered to the patient.
  • a further subject-matter of the invention relates to a method for the treatment and/or prophylaxis of vasomotor symptoms and/or thermoregulatory dysfunctions, such as, for example, the "hot flush" symptom, in a patient, characterized in that an effective amount of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof is administered to the patient.
  • a further subject-matter of the invention relates to a method for the treatment and/or prophylaxis of drug dependencies, medicament dependencies and/or dependencies mediated by other factors, for the treatment and/or prophylaxis of stress caused by the withdrawal of one or more factors mediating the dependency and/or for the treatment and/or prophylaxis of stress-induced relapses in the drug dependencies, medicament dependencies and/or dependencies mediated by other factors, in a patient, characterized in that an effective amount of at least one compound of the general formula (I) or (Ia) and/or pharmaceutically acceptable salt or a prodrug thereof is administered to the patient.
  • a further subject-matter of the invention relates to a method for the treatment and/or prophylaxis of schizophrenia and/or psychosis in a patient, characterized in that an effective amount of at least one compound of the general formula (I) or (Ia) and/or a pharmaceutically acceptable salt or a prodrug thereof is administered to the patient.
  • a further subject-matter of the invention relates to a method as defined above, which is characterized in that the patient is a mammal, preferably a human or a nonhuman mammal or a nonhuman transgenic mammal.
  • a further preferred embodiment relates to compounds of the general formula (I) or (Ia), their tautomers, their prodrugs thereof and their pharmaceutically acceptable salts as described above, which are characterized in that they are selective for the vasopressin receptor subtype V1 b over at least one of the closely related vasopressin/oxytocin receptor subtypes (for example vasopressin Via, vasopressin V2 and/or oxytocin).
  • a further preferred embodiment relates to compounds of the general formula (I) or (Ia), their tautomers, their prodrugs thereof and their pharmaceutically acceptable salts as described above, which are characterized in that they have improved metabolic stability.
  • the metabolic stability of a compound can be determined, for example, by incubating a solution of this compound with liver microsomes from particular species (for example rat, dog or human) and determining the half-life of the compound under these conditions (RS Obach, Curr Opin Drug Discov Devel. 2001 , 4, 36-44). It is possible to conclude from an observed larger half-life that the metabolic stability of the compound is improved.
  • the stability in the presence of human liver microsomes is of particular interest since it makes it possible to predict the metabolic degradation of the compound in the human liver. Compounds with increased metabolic stability (determined in the liver microsome test) are therefore probably also degraded more slowly in the liver.
  • the slower metabolic degradation in the liver can lead to higher and/or longer-lasting concentrations (effective levels) of the compound in the body, so that the elimination half-life of the compounds according to the invention is increased.
  • Increased and/or longer-lasting effective levels may lead to a better efficacy of the compound in the treatment or prophylaxis of various vasopressin-dependent diseases.
  • An improved metabolic stability may additionally lead to an increased bioavailability after oral administration, because the compound is subjected, after being absorbed in the intestine, to less metabolic degradation in the liver (so-called first pass effect).
  • An increased oral bioavailability may, because the concentration (effective level) of the compound is increased, lead to a better efficacy of the compound after oral administration.
  • a further preferred embodiment relates to compounds of the general formula (I) as described above, characterized in that, in patients or relevant animal models allowing prognostic statements on therapeutic application, they have improved pharmacological activity compared to the oxindole compounds known from the prior art.
  • the invention relates in particular to compounds of the general formula (I) which are selected from the group consisting of the examples, listed below, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89 and 90, and also to their tautomeric forms, their prodrugs and in particular their physiologically acceptable salts, and their non-salt forms such as hydrates
  • the invention in particular also relates to the (-)-enantiomers of the Examples 1 to 90 in accordance with the general formula (I) selected from the compounds of the examples, listed below, 1 B, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 1 OB, 1 1 B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 2OB, 21 B, 22B, 23B, 24B, 25B, 26B, 27B, 28B, 29B, 3OB, 31 B, 32B, 33B, 34B, 35B, 36B, 37B, 38B, 39B, 4OB, 41 B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 5OB, 51 B, 52B, 53B, 54B, 55B, 56B, 57B, 58B, 59B, 6OB, 61 B, 62B, 63B, 64B, 65B, 66B, 67B
  • prodrugs is to be understood as meaning those compounds which are metabolized in vivo to the compounds according to the invention. Typical examples of prodrugs are described in CG. Wermeth (Ed.): The Practice of Medicinal Chemistry, Academic Press, San Diego, 1996, pages 671-715. They include, for example, phosphates, carbamates or amino acids, esters and others.
  • suitable prodrugs of the compounds of the formual are compounds of the formula I, where the nitrogen atom that carries R7 is part of an amide/peptide group, i.e. the nitrogen carries a acyl group such as C1-C4-alkylcarbonyl e.g.
  • Such carbamates have been generally described by J. Alexander, R. Cargill, S. R. Michelson, H. Schwam, J. Medicinal Chem. 1988, 31 (2), 318- 322. These groups are cleaved under metabolic conditions to yield a compound of the formula I, wherein R7 is hydrogen.
  • the invention furthermore relates to the pharmaceutically acceptable salts of compounds of the formula I, which are also referred to as physiologically acceptable salts.
  • the salts are generally obtainable by reacting the free base of the compounds (I) according to the invention with a suitable acid.
  • suitable acids are listed, for example, in "Fort Whitneye der Arzneistoffforschung” [Advances in Drug Research], 1966, Birkhauser Verlag, Vol.10, pp.224-285. They include, for example, hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulphonic acid, acetic acid, formic acid, maleic acid and fumaric acid.
  • the compounds of the invention are effective after administration by various routes.
  • the administration can, for example, be carried out intravenously, intramuscularly, subcutaneously, topically, intratracheal ⁇ , intranasally, transdermally, vaginally, rectally, sublingually, buccally or orally and is frequently carried out intravenously, intramuscularly or in particular orally.
  • the present invention also relates to pharmaceutical compositions which comprise a compound (I) of the invention, and/or a tautomer, and/or a pharmaceutically acceptable salt and/or a prodrug thereof and suitable pharmaceutical carriers (drug carriers).
  • suitable pharmaceutical carriers drug carriers.
  • the amount of compound I in the pharmaceutical composition may depend on the formulation type of the composition and may be e.g. in the range from 0.0001 mg/g to 1 g/g in particular from 0.001 mg/g to 0.5 g/g of the composition.
  • These drug carriers are chosen according to the pharmaceutical form and the desired mode of administration.
  • the compounds of the invention of the general formula (I) or, where appropriate, suitable salts of these compounds can be used to manufacture pharmaceutical compositions for oral, sublingual, buccal, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, vaginal or rectal administration and be administered to animals or humans in unit dose forms mixed with conventional pharmaceutical carriers for the prophylaxis or treatment of the above disorders or diseases.
  • Suitable uniform administration forms comprise forms for oral administration, such as tablets, gelatin capsules, powders, granules, solutions or suspensions for oral intake, forms for sublingual, buccal, intratracheal or intranasal administration, aerosols, implants, forms of subcutaneous, intramuscular or intravenous administration and forms of rectal administration.
  • the compounds of the invention can be used in creams, ointments or lotions for topical administration.
  • the dose of the active compound can vary between 0.01 and 50 mg per kg of body weight and per day.
  • Each unit dose may comprise from 0.05 to 5000 mg, preferably 1 to 1000 mg, of the active compound in combination with a pharmaceutical carrier. This unit dose can be administered 1 to 5 times a day so that a daily dose of from 0.5 to 25 000 mg, preferably 1 to 5000 mg, is administered.
  • the active compound is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, silicon dioxide or the like.
  • the tablets can be coated with sucrose, a cellulose derivative or another suitable substance or be treated otherwise in order to display a prolonged or delayed activity and in order to release a predetermined amount of the active compound continuously.
  • a preparation in the form of gelatin capsules is obtained by mixing the active compound with an extender and taking up the resulting mixture in soft or hard gelatin capsules.
  • a preparation in the form of a syrup or elixir or for administration in the form of drops may comprise active compounds together with a sweetener which is preferably calorie-free, methylparaben or propylparaben as antiseptics, a flavouring and a suitable colouring.
  • a sweetener which is preferably calorie-free, methylparaben or propylparaben as antiseptics, a flavouring and a suitable colouring.
  • the water-dispersible powders or granules may comprise the active compounds mixed with dispersants, wetting agents or suspending agents, such as polyvinylpyrrolidones, and sweeteners or taste improvers.
  • Rectal or vaginal administration is achieved by the use of suppositories which are prepared with binders which melt at the rectal temperature, for example cocoa butter or polyethylene glycols.
  • Parenteral administration is effected by using aqueous suspensions, isotonic salt solutions or sterile and injectable solutions which comprise pharmacologically suitable dispersants and/or wetting agents, for example propylene glycol or polyethylene glycol.
  • the active compound can also be formulated as microcapsules or centrosomes, if suitable with one or more carriers or additives.
  • compositions of the invention may comprise further active compounds which may be beneficial for the treatment of the impairments or disorders indicated above.
  • the present invention therefore further relates to pharmaceutical compositions which comprise a plurality of active compounds, where at least one of these is a compound (I) according to the invention, a tautomer, a salt or a prodrug thereof.
  • the preparation of the oxindoles according to the invention can be carried out by different routes as illustrated in synthesis schemes 1 and 2.
  • the variables have the same meanings as in the general formula (I).
  • the 3-hydroxy-1 ,3-dihydroindol-2-ones IV can be obtained by adding metallated heterocycles III to the 3-keto group of the isatins II.
  • the metallated heterocycles such as, for example, the corresponding Grignard (Mg) or organyllithium compound, can be obtained in a customary manner from halogen or hydrocarbon compounds. Exemplary procedures can be found in Houben-Weyl, Methoden der Organischen Chemie [Methods of organic chemistry], Vol. 13, 1-2, Chap. Mg and Li compounds.
  • the isatins Il are either commercially available or were prepared in analogy to methods described in the literature
  • Suitable for use as Pd(O) salts are, for example, transition metal complexes prepared in situ from PdCI 2 or PdOAc 2 by addition of phosphines, such as tris(orthotolyl)phosphine. It is also possible to use commercial palladium complexes, such as, for example, the catalyst tetrakis(triphenylphosphine)palladium(0) and/ or added phosphine ligands.
  • the 3-hydroxyoxindoles IV can be converted into the compounds V which carry a leaving group LG' in position 3, where the leaving group LG' may be a customary leaving group, such as, for example, halide, mesylate or tosylate.
  • a base such as, for example, triethylamine.
  • the compounds V are subsequently reacted with amines, such as, for example, ammonia, which gives the analogous amines Vl after the substitution reactions.
  • Compounds such as Vl can then, after deprotonation with a strong base, such as, for example, potassium tert-butoxide or sodium hydride, in DMF, be converted into the product VIII by treatment with sulphonyl chlorides VII.
  • a strong base such as, for example, potassium tert-butoxide or sodium hydride
  • the sulphonyl chlorides VII used are either commercially available or can be prepared in a manner analogous to known processes (see, for example, J. Med. Chem. 40, 1149 (1997)).
  • the compounds VIII are converted into compounds IX by reaction with reagents for derivatizing amino groups, such as, for example chloroformates, isocyanates or carbamoyl chlorides, generally using customary methods (see J. March, Advanced Organic Chemistry, 1992, 4th edition., Wiley, New York, pages 417-421 ; 499; 903).
  • LG as leaving group may be OPhenyl in the compound IX, which is obtained by reacting VIII with phenyl chloroformate in the presence of a base, such as, for example, pyridine.
  • amines X are either commercially available or can be prepared by methods known from the literature.
  • a further alternative of preparing the amine X is the reaction of amines with aldehydes or ketones in the presence of reducing agents, such as, for example, sodium cyanoborohydride or sodium acetoxyborohydride, in the sense of a reductive amination (J. March, Advanced Organic Chemistry, 1992, 4th edition., Wiley, New York, pages 41 1 ; 898).
  • reducing agents such as, for example, sodium cyanoborohydride or sodium acetoxyborohydride
  • LG' leaving group, such as, for example Cl
  • the order of the synthesis steps for preparing the compounds I according to the invention may be rearranged, analogously to synthesis scheme 1 above.
  • the amino group in the compound Vl is derivatized using, for example, phenyl chloroformate, giving the compounds XIa and/or XIb.
  • the urea derivatives XII are generated which can be converted in the subsequent reaction under otherwise customary conditions by deprotonation of compounds XII using a strong base, such as, for example, sodium hydride or potassium te/f-butoxide, and subsequent treatment with sulphonyl chlorides VII in DMF into the compounds I according to the invention.
  • a strong base such as, for example, sodium hydride or potassium te/f-butoxide
  • the compounds according to the invention can be prepared via various synthesis routes.
  • the procedures mentioned, as described accordingly in synthesis schemes 1 and 2, are only described in greater detail by way of example on the basis of the examples mentioned, without being exclusively limited to the synthesis routes 1 or 2 or analogous procedures mentioned.
  • the solution of the pyridine Grignard reagents was then, over a period of 5-10 minutes, added to the solution, cooled in an ice-bath, of the 5-iodoisatin sodium salt, the temperature fluctuating between 5 and 18°C.
  • the ice-bath was removed, and the reaction mixture was stirred at room temperature for another 2 hours.
  • Excess saturated ammonium chloride solution was added, followed by ethyl acetate, and the mixture was stirred for another 5 minutes.
  • the aqueous phase was removed and extracted with ethyl acetate (2 x).
  • the combined organic phases were washed with water (2 x), and the solvent was removed under reduced pressure.
  • the reaction mixture was transferred directly into a preheated oil bath at a temperature of 100 0 C.
  • the mixture was stirred at 100 0 C (oil bath temperature), and after 30 minutes, another 0.51 g (0.45 mmol) of the catalyst was added. In total, the mixture was stirred for 2 hours.
  • the reaction mixture was cooled to room temperature, and an excess of water was added.
  • the mixture was extracted with ethyl acetate (3 x), and the combined organic phases were washed with water (3 x).
  • the solvent was evaporated to dryness under reduced pressure, and the residue was slurried with small volumes of ethyl acetate. A slightly yellowish solid was removed by filtration, washed with ethyl acetate and dried in a vacuum drying cabinet.
  • the impurities were detected in the organic phase, the product being in the acidic aqueous phase. Accordingly, the aqueous phase was neutralized with 2 N NaOH solution and extracted with ethyl acetate. After drying over magnesium sulphate, filtration and removal of the ethyl acetate under reduced pressure, the product could be crystallized with diethyl ether.
  • reaction mixture was stirred overnight, and the reaction was checked by TLC (silica gel, dichloromethane/methanol 15:5) to determine the progress of the reaction.
  • the reaction was diluted with ethyl acetate and washed with water (1 x) and saturated sodium chloride solution (1 x).
  • the organic phase was dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure. The residue was taken up in a little diethyl ether, and 6 times the amount of cyclohexane was added.
  • a colourless solid comprising 615 mg (1.22 mmol, 86%) of pure N-[5-cyano-3-(2- ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1 /-/-indol-3-yl]-4-(1 -methylpiperidin-4-yl)piperazine-1 - carboxamide precipitated out.
  • the compounds according to Examples 2 to 4 and 6 to 30 can be prepared in a manner analogous to the preparation procedures according to Example 1 and/or Example 5 using the appropriate starting materials.
  • the compounds according to Examples 32 to 36 can be prepared in a manner analogous to the preparation procedures according to Example 1 , 5 and/or 31 using the appropriate starting materials.
  • EXAMPLE 34 ⁇ /-[5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1 -(phenylsulphonyl)-2,3-dihydro-1 H-indol-3-yl]- 4-(4-methylpiperazin-1 -yl)piperidine-1 -carboxamide
  • the combined organic phases were dried over magnesium sulphate and filtered, and the solvent was removed under reduced pressure.
  • the crude mixture was purified initially by column chromatography of silica gel (column 20 x 200 mm) using dichloromethane and 2% methanol as eluents.
  • the combined, still slightly contaminated product fractions were purified again by preparative HPLC on a Chromolith column (normal phase, from Merck) using the eluents dichloromethane and methanol (gradient 0-10% by volume of methanol over 15 min.).
  • the compounds according to Examples 38 to 90 can be prepared in a manner analogous to the preparation procedures according to Examples 1 , 5, 31 , 37, 55, 61 and/or 67 using the appropriate starting materials.
  • EXAMPLE 43 ⁇ /-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3- dihydro-1 /-/-indol-3-yl]-4-(4-propylpiperazin-1 -yl)piperidine-1 -carboxamide
  • N-[5-Cyano- 1 -[(2, 4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2, 3- dihydro- 1 H-indol-3-yl]-4-piperazin- 1 -ylpiperidine-1 -carboxamide 55.3 mg (0.07 mmol) of tert-butyl 4-[1-( ⁇ [5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2- ethoxypyridin-3-yl)-2-oxo-2, 3, -dihydro-1 /-/-indol-3-yl]amino ⁇ carbonyl)piperidin-4- yl]piperazine-1-carboxylate were initially charged in 4 ml of methanol, and 1.0 ml of 5-6 M hydrochloric acid in isopropanol was added.
  • the mixture was stirred at room temperature. The progress of the reaction was monitored by TLC (silica gel, CH 2 CI 2 ZMeOH 9:1 ). After complete conversion, the alcoholic solvent residues were removed, and the residue was taken up in dichloromethane and, using 1 N aqueous sodium hydroxide solution, adjusted by extraction to pH 9. The organic phase was separated from the aqueous phase, and the aqueous phase was reextracted with dichloromethane (2 x). The combined organic phase was dried over magnesium sulphate, and the solvent was removed under reduced pressure. The residue was crystallized from diethyl ether.
  • the residue can also be purified either by conventional column chromatography on a normal phase (NP- SiO 2 cartridge, Chromabond) using dichloromethane/methanol as mobile phases or by preparative HPLC (RP, mobile phases acetonitrile/water, 0.01% TFA) .
  • RP preparative HPLC
  • 15.9 mg (0.023 mmol, 33%) of N-[5-cyano-1-[(2,4- dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1 /-/-indol-3-yl]-4- piperazin-1 -ylpiperidine-1 -carboxamide were isolated.
  • EXAMPLES 25 to 30 and 56 to 60 and 85 to 90 The compounds according to Examples 25 to 30 and 56 to 60 and 85 to 90 can also be prepared in a manner analogous to the preparation procedures according to Examples 1 , 5, 31 , 37 and/or 55 using the appropriate starting materials.
  • EXAMPLE 25 ⁇ /-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3- dihydro-1 /-/-indol-3-yl]-4-piperidin-4-ylpiperazine-1 -carboxamide bis(trifluoroacetate)
  • EXAMPLE 85 ⁇ /-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3- dihydro-1 /-/-indol-3-yl]-4,4'-bipiperidine-1 -carboxamide bis(trifluoroacetate)
  • the substituent R7 can, according to synthesis scheme 1 or 2, also be introduced subsequently by reductive amination, which is to be illustrated in an exemplary manner using Examples 61 and 67:
  • EXAMPLE 61 ⁇ /-[5-Cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3- dihydro-1 /-/-indol-3-yl]-1 '-methyl-4,4'-bipiperidine-1-carboxamide 100 mg (0.138 mmol) of 4-[1-( ⁇ [5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2- ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1 /-/-indol-3-yl]amino ⁇ carbonyl)piperidin-4- yl]piperidinium chloride (corresponds to the chloride salt of Example 85) (prepared according to Example 1 , process steps 1 a) to 1f) and Example 55, process steps 55a) to 55b)
  • reaction mixture was initially diluted with 30 ml of dichloromethane and then extracted with saturated sodium bicarbonate solution (3 x). The combined organic phases were dried over magnesium sulphate and filtered, and the solvent was evaporated under reduced pressure. What was isolated were 75 mg of crude product which was purified by a preparative HPLC on a Chromolith column (RP-18e, from Merck, mobile phases acetonitrile/water, 0.01% acetic acid).
  • Example 1 the separation of the racemates into its enantiomers (Example 1A and 1 B) by separation on a preparative chiral column is shown:
  • Example 1A The enantiomer which eluted first, having a positive optical rotation (Example 1A), could be isolated in a yield of 19 mg (0.03 mmol, 19%) and the enantiomer which followed, having a negative optical rotation (Example 1 B), could be isolated in a yield of 8 mg (0.01 mmol, 8%).
  • the enantiomers A and B can also be prepared using enantiomerically pure precursors and intermediates, for example analogously to synthesis schemes 1 or 2, preferably via synthesis scheme 1.
  • the separation of the racemic mixture into the (+)-enantiomers and (- )-enantiomers can be carried out by chiral preparative chromatography, preferably via the corresponding amine building block Vl.
  • the amines of the general formula X can be prepared according to synthesis scheme 1 or 2 by reductive amination. Hereinbelow, this is shown using the preparation of the amine compound 1-ethyl-4-piperidin-4-ylpiperazine as an example:
  • the dichloromethane was distilled off on a rotary evaporator, and another 200 ml of methanol and 30 ml of the 5-6 M HCI solution in isopropanol were added. After one hour of stirring under reflux, a white suspension formed with strong evolution of gas. Subsequently, a low-viscosity suspension was fomed, which was cooled to room temperature. The precipitate was filtered off with suction and washed with methanol and diethyl ether. After drying, 36 g (1 17 mmol, 87%) of 1-ethyl-4-piperidin-4-ylpiperazine were isolated as chloride salt.
  • Vasopressin V1 b receptor binding assay
  • test substances were dissolved in a concentration of 10 "2 M in DMSO and further diluted to 5x10 "4 M to 5x10 "9 M in DMSO. This series of DMSO predilutions was diluted 1 :10 with assay buffer. The substance concentration was again diluted 1 :5 in the assay mixture (2% DMSO in the mixture).
  • CHO-K1 cells with stably expressed human vasopressin V1 b receptor were harvested and homogenized in 50 mM Tris-HCI and in the presence of protease inhibitors (Roche complete Mini # 1836170) with a Polytron homogenizer at a medium setting for 2x10 seconds and subsequently centrifuged at 40 000 x g for 1 h.
  • the membrane pellet was again homogenized and centrifuged as described and then taken up in 50 mM Tris- HCI, pH 7.4, homogenized and stored in aliquots frozen in liquid nitrogen at -190 0 C.
  • Binding assay The binding assay was carried out by a method based on that of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).
  • the incubation buffer was: 50 mM Tris, 10 mM MgCI 2 , 0.1% BSA, pH 7.4.
  • membranes 50 ⁇ g/ml protein in incubation buffer
  • CHO-K1 cells with stably expressed human V1 b receptors cell line hV1 b_3H2_CHO
  • 1.5 nM 3 H-AVP 8-Arg-vasopressin, PerkinElmer #18479
  • incubation buffer 50 mM Tris, 10 mM MgCI 2 , 0.1% BSA, pH 7.4
  • total binding or additionally with increasing concentrations of test substance (displacement experiment).
  • the nonspecific binding was determined with 1 ⁇ M AVP (Bachem # H1780). All determinations were carried out as triplicate determinations.
  • the binding parameters were calculated by nonlinear regression in SAS.
  • the algorithms of the program operate in analogy to the LIGAND analysis program (Munson PJ and Rodbard D, Analytical Biochem. 107, 220-239 (1980)).
  • the Kd of 3 H-AVP for the recombinant human V1 b receptors is 0.4 nM and was used to determine the Ki value.
  • test substances were dissolved in a concentration of 10 "2 M in DMSO. These DMSO solutions were further diluted in incubation buffer (50 mM Tris, 10 mM MgCI 2 , 0.1 % BSA, pH 7.4).
  • Membrane preparation CHO-K1 cells with stably expressed human vasopressin Via receptor (clone 5) were harvested and homogenized in 50 mM Tris-HCI and in the presence of protease inhibitors (Roche complete Mini # 1836170) with a Polytron homogenizer at a medium setting for 2x10 seconds and subsequently centrifuged at 40 000 x g for 1 h. The membrane pellet was again homogenized and centrifuged as described and then taken up in 50 mM Tris- HCI, pH 7.4, homogenized and stored in aliquots frozen in liquid nitrogen at -190 0 C.
  • protease inhibitors Roche complete Mini # 1836170
  • the binding assay was carried out by a method based on that of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).
  • the incubation buffer was: 50 mM Tris, 10 mM MgCI 2 , 0.1% BSA, pH 7.4.
  • membranes (20 ⁇ g/ml protein in incubation buffer) from CHO-K1 cells with stably expressed human Via receptors (cell line hV1 a_5_CHO) were incubated with 0.04 nM 125 I-AVP (8-Arg-vasopressin, NEX 128) in incubation buffer (50 mM Tris, 10 mM MgCI 2 , 0.1 % BSA, pH 7.4) (total binding) or additionally with increasing concentrations of test substance (displacement experiment). The nonspecific binding was determined with 1 ⁇ M AVP (Bachem # H 1780). Triplicate determinations were carried out. After incubation (60 minutes at room temperature), the free radioligand was removed by vacuum filtration (Skatron cell harvester 7000) through Wathman GF/B glass fibre filter mats, and the filters were transferred into scintillation vials.
  • the binding parameters were calculated by nonlinear regression in SAS.
  • the algorithms of the program operate in analogy to the LIGAND analysis program (Munson PJ and Rodbard D, Analytical Biochem. 107, 220-239 (1980)).
  • the Kd of 125 I-AVP for the recombinant hV1a receptors was determined in saturation experiments.
  • a Kd of 1.33 nM was used to determine the Ki value.
  • test substances were dissolved in a concentration of 10 "2 M in DMSO. This DMSO solution was further diluted in incubation buffer (50 mM Tris, 10 mM MgCI 2 , 0.1 % BSA, pH 7.4).
  • CHO-K1 cells with stably expressed human vasopressin V2 receptor (clone 23) were harvested and homogenized in 50 mM Tris-HCI and in the presence of protease inhibitors (Roche complete Mini # 1836170) with a Polytron homogenizer at a medium setting for 2x10 seconds and subsequently centrifuged at 40 000 x g for 1 h. The membrane pellet was again homogenized and centrifuged as described and then taken up in 50 mM Tris- HCI, pH 7.4, homogenized and stored in aliquots frozen in liquid nitrogen at -190 0 C.
  • the binding assay was carried out by a method based on that of Tahara et al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).
  • the incubation buffer was: 50 mM Tris, 10 mM MgCI 2 , 0.1% BSA, pH 7.4.
  • membranes 50 ⁇ g/ml protein in incubation buffer
  • CHO-K1 cells with stably expressed human V2 receptors cell line hV2_23_CHO
  • 1-2 nM 3 H-AVP 8-Arg-vasopressin, PerkinElmer #18479
  • the nonspecific binding was determined with 1 ⁇ M AVP (Bachem # H 1780). Triplicate determinations were carried out. After incubation (60 minutes at room temperature), the free radioligand was removed by vacuum filtration (Skatron cell harvester 7000) through Wathman GF/B glass fibre filter mats, and the filters were transferred into scintillation vials.
  • the binding parameters were calculated by nonlinear regression in SAS.
  • the algorithms of the program operate in analogy to the LIGAND analysis program (Munson PJ and Rodbard D, Analytical Biochem. 107, 220-239 (1980)).
  • the Kd of 3 H-AVP for the recombinant hV2 receptors is 2.4 nM and was used to determine the Ki value.
  • V1 b receptor in comparison with V2 receptor, which, expressed as K,(h-V2)/K
  • the substances were dissolved in a concentration of 10 "2 M in DMSO and diluted with incubation buffer (50 mM Tris, 10 mM MgCI 2 , 0.1 % BSA, pH 7.4).
  • HEK-293 cells with transiently expressing recombinant human oxytocin receptors were centrifuged at 750 x g and at room temperature for 5 minutes. The residue was taken up in ice-cold lysis buffer (50 mM Tris-HCI, 10% glycerol, pH 7.4 and Roche Complete Protease Inhibitor) and subjected to an osmotic shock at 4 0 C for 20 minutes. The lyzed cells were then centrifuged at 750 x g and at 4°C for 20 minutes, the residue was taken up in incubation buffer, and aliquots of 10 7 cells/ml were prepared. The aliquots were frozen at -80 0 C until used.
  • ice-cold lysis buffer 50 mM Tris-HCI, 10% glycerol, pH 7.4 and Roche Complete Protease Inhibitor
  • the binding parameters were calculated by nonlinear regression analysis (SAS), in analogy to the LIGAND program of Munson and Rodbard (Analytical Biochem 1980; 107: 220-239).
  • SAS nonlinear regression analysis
  • the Kd of 3 H-oxytocin for the recombinant hOT receptors is 7.6 nM and was used to determine the Ki value.
  • the metabolic stability of the compounds of the invention was determined in the following assay.
  • test substances are incubated in a concentration of 0.5 ⁇ M as follows: 0.5 ⁇ M test substance is preincubated together with liver microsomes of various species (rat, human or other species) (0.25 mg of microsomal protein/ml) in 0.05M potassium phosphate buffer pH 7.4 in microtitre plates at 37°C for 5 min. The reaction is started by adding NADPH (1 mg/ml). 50 ⁇ l aliquots are taken after 0, 5, 10, 15, 20 and 30 min, and the reaction is stopped immediately with the same volume of acetonitrile and cooled down. The samples are frozen until analyzed. Using MSMS, the remaining concentration of undegraded test substance is determined.
  • the half-life (T1/2) is determined, where the half-life of the test substance can be calculated, assuming first order kinetics, from the decrease in the concentration of the compound with time.
  • 150 ⁇ l of rat or human plasma, with 1 or 10 ⁇ M of test substance added, is pipetted onto one side of the 96-well dialysis chambers, 150 ⁇ l of PPS buffer are pipetted onto the other side.
  • the chambers are separated by a dialysis membrane having a cut-off of 6-8000 dalton.
  • the 96-well dialysis chambers are covered and gently shaken overnight.
  • 0.4 mg/ml of human liver microsomes are preincubated for 10 minutes with the test substances to be tested (0-20 ⁇ M), the CYP specific substrates, in 0.05 M potassium phosphate buffer pH 7.4 at 37°C.
  • the Cyp-specific substrate for CYP 2C9 is luciferin H, that for CYP 3A4 is luciferin BE.
  • the reaction is started by addition of NADPH. After 30 min of incubation at RT, the luciferin detection reagent is added, and the resulting luminescence signal is measured (modified according to literature reference: Promega, Technical Bulletin P450-GLO TM Assays).
  • Preincubation 0.05 mg/ml of microsomal protein (human liver microsomes) are preincubated with 0-10 ⁇ M (or 50 ⁇ M) of test substance in 50 mM potassium phosphate buffer for 5 min. The reaction is started using NADPH. After 30 min, 4 ⁇ M of midazolam (final concentration) are added, and the mixture is incubated for a further 10 min. After 10 min, 75 ⁇ l of the reaction solution are removed and quenched with 150 ⁇ l of acetonitrile solution.
  • microsomal protein human liver microsomes
  • 4 ⁇ M midazolam final concentration
  • 0-10 ⁇ M or 50 ⁇ M
  • test substance 0.05 mg/ml of microsomal protein (human liver microsomes), 4 ⁇ M midazolam (final concentration) and 0-10 ⁇ M (or 50 ⁇ M) of test substance are preincubated in 50 mM potassium phosphate buffer for 5 min.
  • the reaction is started using NADPH. After 10 min, 75 ⁇ l of the reaction solution are removed and quenched with 150 ⁇ l of acetonitrile solution. The samples are frozen until analyzed by MSMS (modified according to literature references:
  • the solubility in water of the compounds according to the invention can be determined, for example, according to the so-called "shake flask” method (according to ASTM International: E 1148-02, Standard test methods for measurement of aqueous solubility, Book of Standards Volume 11.05.).
  • a buffer solution having a certain pH for example phosphate buffer pH 7.4
  • the resulting mixture is shaken or stirred until the steady state has been reached (typically 24 or 48 hours, sometimes even up to 7 days).
  • the undissolved solid is then removed by filtration or centrifugation, and the concentration of the dissolved compound is determined by UV spectroscopy or high-pressure liquid chromatography (HPLC) using an appropriate calibration curve.

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Abstract

La présente invention concerne de nouveaux dérivés d'oxindole de formule générale (I), des médicaments les comprenant et leur utilisation pour la prévention et/ou le traitement de maladies dépendant de la vasopressine.
PCT/EP2007/064622 2006-12-30 2007-12-28 Dérivés d'oxindole substitués et leur utilsiation comme lignads du récepteur de la vasopressine WO2008080973A1 (fr)

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UAA200908025A UA96785C2 (uk) 2006-12-30 2007-12-28 Заміщені похідні оксиндолу та їх застосування як лігандів рецептора вазопресину
MX2009007104A MX2009007104A (es) 2006-12-30 2007-12-28 Derivados de oxindol sustituido y su uso como ligandos del receptor de vasopresina.
JP2009543480A JP5318781B2 (ja) 2006-12-30 2007-12-28 置換オキシインドール誘導体及びバソプレッシン受容体リガンドとしてのその使用
US12/521,713 US8815868B2 (en) 2006-12-30 2007-12-28 Substituted oxindole derivatives and their use as vasopressin receptor ligands
BRPI0720866-9A2A BRPI0720866A2 (pt) 2006-12-30 2007-12-28 Derivados de oxindol substituídos e seu uso como ligandos de receptor de vasopressina
CN200780051459.2A CN101611028B (zh) 2006-12-30 2007-12-28 取代的羟吲哚衍生物、以及它们用作加压素受体配体的用途
EP07866324.2A EP2114923B1 (fr) 2006-12-30 2007-12-28 Dérivés d'oxindole substitués et leur utilsiation comme ligands du récepteur de la vasopressine
ES07866324.2T ES2523320T3 (es) 2006-12-30 2007-12-28 Derivados de oxindol sustituido y su uso como ligandos del receptor de vasopresina
AU2007341236A AU2007341236B2 (en) 2006-12-30 2007-12-28 Substituted oxindole derivatives and their use as vasopressin receptor ligands
NZ577720A NZ577720A (en) 2006-12-30 2007-12-28 Substituted oxindole derivatives and their use as vasopressin receptor ligands
CA2673584A CA2673584C (fr) 2006-12-30 2007-12-28 Derives d'oxindole substitues et leur utilsiation comme lignads du recepteur de la vasopressine
KR1020097016052A KR101485326B1 (ko) 2006-12-30 2007-12-28 치환된 옥신돌 유도체 및 바소프레신 수용체 리간드로서의 이의 용도
IL199265A IL199265A (en) 2006-12-30 2009-06-09 Oxindol derivatives are converted and used to make a drug
ZA2009/04363A ZA200904363B (en) 2006-12-30 2009-06-22 Substituted oxindole derivatives and their use as vasopressin receptor ligands
HK10100154.0A HK1132740A1 (en) 2006-12-30 2010-01-08 Substituted oxindole derivatives and their use as vasopressin receptor ligands
US13/590,261 US8859557B2 (en) 2006-12-30 2012-08-21 Substituted oxindole derivatives and their use as vasopressin receptor ligands
US14/481,847 US20140378471A1 (en) 2006-12-30 2014-09-09 Substituted oxindole derivatives and their use as vasopressin receptor ligands
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WO2013186399A1 (fr) * 2012-06-15 2013-12-19 Holsboermaschmeyer Neuro Chemie Gmbh Antagoniste du récepteur v1b destiné à être utilisé dans le traitement de patients présentant un taux élevé d'avp et/ou un taux élevé de copeptine
US8815868B2 (en) 2006-12-30 2014-08-26 Abbott Gmbh & Co. Kg Substituted oxindole derivatives and their use as vasopressin receptor ligands
WO2014140186A1 (fr) 2013-03-14 2014-09-18 AbbVie Deutschland GmbH & Co. KG Dérivés d'oxindole à substituant oxétane et leur utilisation pour le traitement de maladies liées à la vasopressine
US9040568B2 (en) 2009-05-29 2015-05-26 Abbvie Inc. Pharmaceutical compositions for the treatment of pain
WO2015091931A1 (fr) 2013-12-20 2015-06-25 AbbVie Deutschland GmbH & Co. KG Dérivés d'oxindole à substituant azétidinyl substitué par pipéridyl, et leur utilisation pour le traitement de maladies liées à la vasopressine
US9186407B2 (en) 2006-12-12 2015-11-17 Abbvie Inc. Pharmaceutical compositions and their methods of use
WO2015173392A1 (fr) 2014-05-15 2015-11-19 AbbVie Deutschland GmbH & Co. KG Dérivés d'oxindole à substituant spiro à liaison co, et leur utilisation pour le traitement de maladies liées à la vasopressine
KR101570996B1 (ko) 2007-12-27 2015-11-23 아비에 도이치란트 게엠베하 운트 콤파니 카게 치환된 옥시인돌 유도체 및 바소프레신 의존성 질병을 치료하기 위한 이의 용도
US9273036B2 (en) 2013-03-14 2016-03-01 AbbVie Deutschland GmbH & Co. KG Oxindole derivatives carrying an oxetane substituent and use thereof for treating vasopressine-related diseases
US9487505B2 (en) 2003-09-30 2016-11-08 AbbVie Deutschland GmbH & Co. KG Heteroaryl-substituted 1,3-dihydroindol-2-one derivatives and medicaments containing them
US9862704B2 (en) 2013-12-20 2018-01-09 AbbVie Deutschland GmbH & Co. KG Oxindole derivatives carrying an amine-substituted piperidyl-acetidinyl substituent and use thereof for treating vasopressine-related diseases
US10190168B2 (en) 2013-06-17 2019-01-29 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Method for predicting a treatment response to a CRHR1 antagonist and/or a V1B antagonist in a patient with depressive and/or anxiety symptoms
US10377746B2 (en) 2015-11-06 2019-08-13 Hoffmann-La Roche Inc. Indolin-2-one derivatives
US10457667B2 (en) 2015-11-06 2019-10-29 Hoffmann-La Roche Inc. Indolin-2-one derivatives
US10519140B2 (en) 2015-11-06 2019-12-31 Hoffmann-La Roche Inc. Indolin-2-one derivatives
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